Microglia are brain-resident macrophages responsible for immune surveillance. These cells become activated in response to injury, infection, environmental toxins, and other stimuli, thereby critically influencing neuronal survival and brain function. A wealth of clinical and experimental data implicate chronic microglia activation and overproduction of inflammatory mediators in the pathogenesis of Parkinson's disease (PD), the pathological hallmark of which is loss of ventral midbrain dopaminergic (DA) neurons that control output from motor cortex. However, the key molecular regulators of neuroinflammatory responses in the ventral midbrain have yet to be identified. The goals of this proposal are to investigate the role of Regulator of G-protein Signaling (RGS)-10, a GTPase Accelerating Protein (GAP) enriched in microglia, in neuroinflammatory responses that influence the vulnerability of nigral DA neurons to inflammation-induced degeneration. In Specific Aim 1 we will investigate the role of RGS10 in microglia activation and impact on survival of dopaminergic neurons using cell-based and rodent models. In Specific Aim 2, we will define the molecular mechanism and signaling pathways involved in RGS10-dependent regulation of activation responses and gene expression in microglia using cell-based models. In Specific Aim 3 we will investigate the extent to which aging and neurodegeneration affect mouse and human RGS10 expression in microglia and peripheral macrophages. Completion of the proposed experiments will provide new information regarding the function of RGS10 in microglia and in neuroinflammatory responses in the ventral midbrain and may reveal novel targets for development of new therapies to prevent or treat PD, the second most common neurodegenerative disorder in the U.S.